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The Role of MRAs in CKD and CV Treatment


Dr Agarwal provides a deep dive into the use of nonsteroidal mineralocorticoid receptor antagonists in CKD therapy.

Ryan Haumschild, PharmD, MS, MBA: This is an exciting time. The first-in-class nonsteroidal mineralocorticoid receptor antagonist [MRA], finerenone, was approved in July 2021 based on the positive results of the phase 3 FIDELIO-DKD study. We want to talk about the introduction of this new therapy and how it broadens the treatment landscape for patients with CKD [chronic kidney disease] and potentially cardiovascular [CV] disease. Dr Agarwal, do you want to talk a little about this study and this new treatment? If you could, also talk about the follow-up study, FIGARO-DKD, which demonstrated its ability to improve cardiovascular outcomes and the strong association between CKD and cardiovascular risk. How do data from this study impact the treatment and management strategies for this patient population?

Rajiv Agarwal, MD, MS: In the first trial, FIDELIO-DKD, we look at the kidney failure outcome. In the second trial, FIGARO-DKD, we’ll look at the cardiovascular protection outcome. All these patients had type 2 diabetes. The kidney failure outcome had been looked at numerous times before, for example in RENAAL, IDNT, and CREDENCE was ongoing at that time. We had no information then, but at least we know that IDNT and RENAAL worked.

FIDELIO-DKD was done in a group of patients who had more advanced kidney disease, so they were limited to a GFR [glomerular filtration rate] between 25 and 75 mL/min, and had to have a UACR [urine albumin-to-creatinine ratio] between 30 and 5000 mg/g. These patients were excluded if they had heart failure with reduced ejection fraction because there’s level 1A evidence that spironolactone was effective in these patients. They also required them to have up to a 16-week run in, during which ACE [angiotensin-converting enzyme] inhibitors or ARBs [angiotensin receptor blockers] were maximized, and they also excluded people who had potassium of more than 4.8 mmol/L at screening at baseline to get into the trial. They selected a population that they thought would benefit from the drug.

We were walking on eggshells here. We didn’t know whether it was going to work because we had 2 negative trials, and everybody was laughing and saying, “You’re still continuing these trials?” Then when the trial results came out, we had hit the primary end point, the kidney failure outcome, and we also hit the secondary outcome, the cardiovascular outcome, which were both positive.

Even though it’s an MRA, it isn’t spironolactone. That’s a hugely positive result of FIDELIO-DKD, and that’s the basis for the FDA approval of the drug in July 2021 for the use in people with type 2 diabetes and kidney disease for the prevention of myocardial infarction [MI], stroke, cardiovascular death, and kidney failure. That’s basically the indication of the drug. They hadn’t even seen the FIGARO-DKD data.

FIGARO-DKD is the more ambitious trial, because it’s looking at protection of cardiovascular outcomes in people who have simply kidney disease. We’re saying that if you have kidney disease and type 2 diabetes, you are at heightened cardiovascular risk, and you can reduce that risk if you use finerenone. There’s a 14% relative risk reduction on top of other standard of care. People are getting solid therapies. Their baseline blood pressure is about 138 mm Hg, their A1C [glycated hemoglobin] is about 7.7%, and about 71% of these patients are on statins. Everybody is on ACEs or ARBs. This drug on top of other effective therapies is reducing the relative risk by 14% in cardiovascular outcomes. That risk is primarily driven by reduction in heart failure outcomes. It isn’t by reducing MIs or strokes, but mostly heart failure outcomes and reduction in CV deaths. That’s where the major signal is for this drug.

The thing to appreciate about this drug is that 62% of the patients in the FIGARO-DKD trial had a GFR above 60 mL/min. If you’re screening these patients based on GFR, you aren’t going to make any impact. This drug is for primary care physicians, not for cardiologists or nephrologists alone. It would work in your cardiology or nephrology practice, but if you’re looking at a patient with type 2 diabetes with albuminuria, that’s where you want to start using the drug, because you’re reducing the risk of heart failure hospitalizations and kidney failure.

The FIGARO-DKD trial didn’t meet its primary end point of the kidney failure. But if you look at the outcome of 57% reduction in eGFR [estimated glomerular filtration rate], ESRD [end-stage renal disease], or renal death, and a 57% reduction in eGFR is a doubling of serum creatinine. That’s the criteria we used in RENAAL, IDNT, and CREDENCE. If you use those criteria, you have a 23% relative risk reduction in that outcome, which is statistically significant.

In effect, it’s a glitch in the way we’re defining the outcomes. But if you define the outcome using the more conventional way, we still have a positive outcome for kidney failure. It’s telling you that on top of existing therapy, you can reduce cardiovascular risk and kidney failure risk in people with type 2 diabetes and chronic kidney disease. It has expanded the population. About 1000 patients in this trial were on an SGLT2 inhibitor. If you exclude those patients and reanalyze the data, the data don’t change. In other words, it wasn’t flying because people were on SGLT2 inhibitors. But if you include those data and look at only the population of patients who are on baseline SGLT2 inhibitors, the point estimate of the hazard ratio is 0.63. It’s even lower than the point estimate when you aren’t on an SGLT2. With the hazard ratio, the upper bound is 1, which is protective even in the presence of SGLT2 inhibitors. When you use these 2 drugs in combination, we have found with the SGLT2 inhibitor in our post hoc analyses that the risk of hyperkalemia appears to be mitigated when we use them together.

That’s what we have learned about these trials. [This is] a new class of drug. There’s nothing on the horizon that’s being developed, because most of the companies that were using nonsteroidal MRAs have walked out. We have other trials that are going to be done, including the FINE-CKD trial, which is looking at the slope of CKD in people who don’t have diabetes. Another trial, FINEARTS-HF, is looking at people with heart failure with preserved injection fraction and their outcomes. There are more data to come, but it’s an amazing advance, especially to help people with type 2 diabetes and CKD.

Transcript edited for clarity.

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